We propose to evaluate the use of the Newcastle disease virus (NDV) as a delivery vector for host immunization with borrelial antigens as vaccine targets. We will assess protection of NDV-immunized rodent hosts against Borrelia burgdorferi infection, known as Lyme disease or Lyme borreliosis. NDV is an avian virus that is highly immunogenic yet attenuated in mammals including primates. NDV is a safe vaccine vector for human use and anti-NDV antibodies are readily induced in human, as shown in clinical trial studies. Infectious NDV can be easily produced from transfected cDNAs by reverse genetics, a method that has been instrumental for studying basic biology and pathogenesis of the virus. In recent years, these technologies are also adopted for studies with translational goals, such as engineering NDV vectors against variety of animal and human diseases. In this proposal, we will assess if NDV-derived vectors could be an additional approach for host immunization against B. burgdorferi infection and identify protective efficacy of several newly characterized novel spirochete antigens. Our current data show that even a single immunization of rodents with recombinant NDV elicits a robust antibody response against tested borrelial antigens. We will initiate additional series of immunization studies with NDV constructs carrying several new target antigens, assess antibody development in rodent hosts and finally determine if specific antibodies in the host interfere with spirochete infectivity. If more than one antigen is promising we will combine multiple antigens in search of an additive effect. We will also perform studies for understanding the mechanism of humoral and cellular immune responses associated with host protection. Overall, these studies will contribute to the development of preventive measures against multi-organ infection caused by B. burgdorferi.